6-fluoroallopregnane-3,20-diones and 6-fluoropregnane-3,20-diones



United States PatentO 6-FLUOROALLOPREGNANE3,20-DIONES AND fi-FLUOROPREGNANE-S,Z-DIONFS 1 Allan Campbell, Kalamazoo Township, Kalamazoo County, John 'C. Babcock,.Portage Township, Kalamazoo County, and John A. Hogg, Kalamazoo Township, Kalamazoo County,Mich., assignors to The Upjohn CompanyqKalamaZoo, Mich., a corporation of Michigan No Drawing. Application June 9, 1958 Serial No. 740,552

7 Claims. (CI. 260-3973) The present invention relates to novel Ga-fllIOl'O and 6,8-fluoro steroids and is more particularly concerned with novel 6-fiuoroallopregnane-3,20-dionesand 6-'fluoropregnane-3,20-diones. V i

The novel compounds ofthis inventioncan berepresented by the formula:

In this application the wavy line Q) when appearing at the 6-position is a generic expression inclusive of the alpha ((1) and beta (,8) configuration.

The novel products of this invention, the compounds of Formula I, possess useful pharmacologic properties. The compounds of Formula I possess central-nervoussystem regulating properties of improved therapeutic ratio, sedative-hypnotic properties, and anesthetic properties and are accordingly useful adjuncts in the production of anesthesia as well as in aberrant psychological states. Further, they have valuable mineral-regulating and anti-estrogenic properties.

The novel compounds and the process of the present invention are illustratively represented by the following formulae:

CH; CHI

(3113 CH; C=O =0 CH; OH:

H ---r I 3 i F F The starting steroids for the process of the present in vention, the compounds of Formula II, such as 6a-fluoro- 4-pregueue-3,20-dione and 6fl-fluoro-4-pregnene-3,20- dione, are prepared in accordance with the procedures disclosed in our copending application Serial No. 699,504, filed November 29, 1957, now Patent No. 2,838,528 issued June 10, 1958.

The process of the present invention comprises hydrogenation of the 4,5-double bond of a 6-fluoro-4-pregnenea 2,878,268 Patented Mar. 17, 1959 steroid, catalyst and supporting media can be contacted together in a solvent medium prior to introduction of the hydrogen. It is not necessary to conduct the :reaction under pressure, although, when pressure is utilized, a hydrogen pressure of about one to pounds per square inch gauge or more is operative, a pressure of from about twenty to forty pounds per square inch gauge prefcrred. Any suitable temperature between about zero and 100 degrees centigrade may be employed, with room temperature being satisfactory. Hydrogenationis continued until approximately one molar equivalent of hy drogen has been absorbed. The catalyst is then separated from the solution by filtration and the hydrogenated products are isolated by removal of thesolvent'. Usually the crude hydrogenation product is a mixture containing both the normal and the allo isomers, i. e.,. fluoropregnane-3,20-dione and ,6-fiuoroallopregnane-3,ZU-dione. The isomers are separated by conventional means such as for example, fractional crystallization or chromatog raphy. Alternatively the normal and allo isomers can be conveniently separated by reaction of the mixture with pyrrolidine to form the 3-pyrrolidyl enamine. The 3-pyr rolidyl enamines of the allo and normal isomers possess different solubility properties and may be separated by crystallization from methanol, ether, ethyl acetate, pyridine or the like. After separation, for example, by filtration, the enamine group is removed by treating the crystalline enamine and its mother liquor separately with the base or with water to regenerate the 3-ketone, producing the corresponding 6-fluoropregnane-3,20-dione and 6-fluoroa1lopregnane-3,ZO-dione.

This application is a continuation-in-part of application Serial No. 699,504, filed November 29, 1957.

The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

EXAMPLE 1 6a-fluoroallopregnane-3,20-dione and 6a-fluoropregnane- 3,20-dione A mixture of 1.0 gram of 6a-fiuoro-4-pregnene-3fl0 dione, 100 milliliters of 95 percent ethanol, 0.1 gram of five percent palladium on charcoal and one drop of 6 N hydrochloric was shaken under hydrogen pressure. After twelve minutes the pressure became constant. The reaction mixture was filtered and the filtrate obtained was neutralized with one drop of pyridine. The solvent was removed under vacuum to give a residue. The residue was recrystallized three times from acetone-Skellysolve B hexanes to give milligrams of oa-fiuoroallopregnane- 3,20-dione having a melting point of 192 to 196 degrees centigrade and an [ab plus 118 degrees in chloroform.

Analysis.-Calculated for C H FO C, 75.18; H, 9.62; F, 5.66. Found: C, 75.54; H, 9.08; F, 6.10.

oa-fluoropregnane-3,20-dione is present in the crystallization mother liquors and can be recovered by additional fractional crystallization or chromatography, followed by recrystallization from acetone-Skellysolve B hexanes.

Alternatively, the two isomers can be separated by reaction of the crude residue mixture from the hydrogenation with three milliliters of pyrrolidine in 25 milli- 1 3,20-dione.

liters of methanol at reflux temperature and under an atmosphere of nitrogen for about two minutes. The 3-pyrrolidyl enamines of the allo and normal compounds thusformed are then separated by crystallization. The first crop of crystals of the 3-pyrrolidy1 enamine which forms is removed, and is dissolved by adding thereto 200 milliliters of methanol containing ten milliliters of ten percent. sodium hydroxide solution and warming under a nitrogen atmosphere at approximately fifty degrees centigrade for about twenty minutes. The mother liquor, H i

containing the remaining 3-pyrrolidyl enamine, which is left following removal of the first crop of crystals, has .added thereto 175- milliliters of methanol containing ten 3 milliliters of ten percent sodium hydroxide solution fol- \lowe d by warming at approximately fifty degrees centigrade under a nitrogen atmosphere for about twenty minutes. The solutions are then cooled, neutralized with acetic acid and concentrated to near dryness under reduced pressure. The residues thus obtained are extracted with .ether and the ether extract is washed, dried, and evap- ,orated to dryness. Crystallizations from acetone-SkellysolveB hexanes give the pure allo and normal isomers,

6m-fluoroallopregnane-3,20-dione and fie-fluoropregnane- 73,2Q-dione, respectively.

Following the hydrogenation and separation procedures described above, but substituting 6fi-fluoro-4-pregnene- .3,20-dione as starting material therein, is productive of It is to be understood that the invention is not to be ,7 limited to the exact details of operation or exact com- 6-fluoroallopregnane-3,20 dione.

. 6a-fluoroallopregnane-3,ZO-dione. 6B-fluoroallopregnane-3,ZO-dione., 6-fluoropregnane-3,ZO-dione. 6u-fluoropregnane-3,ZO-dione.

. 6,8-fluoropregnane-3,20-dione.

References Cited in the file of this patent UNITED STATES PATENTS 2,838,528 Campbell et a1. June 10, 1958 

1. A 6-FLUORO COMPOUND OF THE FOLLOWING FORMULA: 